scholarly journals The Role of Ku70 as a Cytosolic DNA Sensor in Innate Immunity and Beyond

2021 ◽  
Vol 11 ◽  
Author(s):  
Hongyan Sui ◽  
Ming Hao ◽  
Weizhong Chang ◽  
Tomozumi Imamichi
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Nuclear Protein ◽  
Repair Process ◽  
Innate Immune ◽  
Extracellular Dna ◽  
Functional Study ◽  
Dna Sensor

Human Ku70 is a well-known endogenous nuclear protein involved in the non-homologous end joining pathway to repair double-stranded breaks in DNA. However, Ku70 has been studied in multiple contexts and grown into a multifunctional protein. In addition to the extensive functional study of Ku70 in DNA repair process, many studies have emphasized the role of Ku70 in various other cellular processes, including apoptosis, aging, and HIV replication. In this review, we focus on discussing the role of Ku70 in inducing interferons and proinflammatory cytokines as a cytosolic DNA sensor. We explored the unique structure of Ku70 binding with DNA; illustrated, with evidence, how Ku70, as a nuclear protein, responds to extracellular DNA stimulation; and summarized the mechanisms of the Ku70-involved innate immune response pathway. Finally, we discussed several new strategies to modulate Ku70-mediated innate immune response and highlighted some potential physiological insights based on the role of Ku70 in innate immunity.

T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese

2021 ◽  
Vol 118 (42) ◽  
pp. e2103526118
Author(s):  
Lingfang Zhu ◽  
Lei Xu ◽  
Chenguang Wang ◽  
Changfu Li ◽  
Mengyuan Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Metal Ions ◽  
Innate Immune Response ◽  
Metal Ion ◽  
Innate Immune ◽  
Host Cells ◽  
Host Innate Immune Response ◽  
Host Innate Immunity

Cellular ionic concentrations are a central factor orchestrating host innate immunity, but no pathogenic mechanism that perturbs host innate immunity by directly targeting metal ions has yet been described. Here, we report a unique virulence strategy of Yersinia pseudotuberculosis (Yptb) involving modulation of the availability of Mn2+, an immunostimulatory metal ion in host cells. We showed that the Yptb type VI secretion system (T6SS) delivered a micropeptide, TssS, into host cells to enhance its virulence. The mutant strain lacking TssS (ΔtssS) showed substantially reduced virulence but induced a significantly stronger host innate immune response, indicating an antagonistic role of this effector in host antimicrobial immunity. Subsequent studies revealed that TssS is a Mn2+-chelating protein and that its Mn2+-chelating ability is essential for the disruption of host innate immunity. Moreover, we showed that Mn2+ enhances the host innate immune response to Yptb infection by activating the stimulator of interferon genes (STING)-mediated immune response. Furthermore, we demonstrated that TssS counteracted the cytoplasmic Mn2+ increase to inhibit the STING-mediated innate immune response by sequestering Mn2+. Finally, TssS-mediated STING inhibition sabotaged bacterial clearance in vivo. These results reveal a previously unrecognized bacterial immune evasion strategy involving modulation of the bioavailability of intracellular metal ions and provide a perspective on the role of the T6SS in pathogenesis.

Bone Marrow Cell Rejection by Innate Immune Pathways Is Exclusively Dependent On the TRIF Pathway.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3526-3526
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Lala-Rukh Hussain ◽  
Yiming Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Solid Organ ◽  
Allogeneic Bone ◽  
Wild Type ◽  
Donor Chimerism

Abstract Abstract 3526 Poster Board III-463 Research on transplantation rejection, tolerance, and immunosuppressive agents has been directed toward the adaptive immune response as, until now, it has been believed to be the dominant mechanism for alloreactivity. The role of innate immunity in transplantation has not been fully defined. Despite the sentinel role of innate immunity in driving and shaping adaptive immunity, the contribution of innate immunity to bone narrow cells has only recently been identified. TLR4-driven MyD88-dependent immunity has been demonstrated to be critical for allogeneic innate immune responses to solid organ transplants. Whether innate immunity plays a role in BMC rejection has not been defined. In the present studies we tested whether the absence of MyD88 would enhance allogeneic engraftment in bone marrow transplantation (BMT). The core component of TLR signaling is activation of an IL-1-like pathway dependent upon the adapter MyD88. MyD88−/− B6 mice (n=6) were used to study the role of MyD88 signaling in allogeneic BMC rejection. As TRIF is another crucial adapter for TLR3 signaling and responsible for induction of signaling via type 1 IFNs, B6 TRIF−/− mice (n=6) were also investigated. Wild-type B6 (H2b, n=6) mice were used as controls. In the present study, MHC plus minor antigen-disparate BALB/c (H2d) mice served as allogeneic bone marrow donors. Recipients were nonmyeloablatively conditioned with anti-CD154 mAb (day0 and +3) to block CD40:CD154 co-stimulatory pathway and sirolimus (day0 to +4) to block late-stage T cell activation by inhibiting IL-2 responsiveness. Recipients were transplanted with 15 × 106 allogeneic (BALB/c; H2d) marrow cells 4-6 hours following conditioning with 100 cGy total body irradiation (TBI). Allogeneic engraftment was achieved in 33.3% of MyD88−/− recipients at 1 mo after BMT, a percentage similar to that for wild-type B6 mice. Surprisingly, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month after BMT, which was significantly higher than in MyD88−/− (1.8 ± 1.0%; P < 0.0001) or in wild-type B6 mice (1.3 ± 0.8%; P < 0.005) and thereafter through all time points tested (2, 4 and 5 months, P < 0.05). The levels of donor chimerism increased with time and the level of donor chimerism reached 14.7 ± 7.1% TRIF−/− at five months. These results suggest that allogeneic BMC rejection is uniquely independent of the MyD88 pathway but rather involves TRIF signaling. These data suggest that the innate immune response to BMC differs from that for solid organs and may reflect the specificity of BMT compared with other transplants. These findings demonstrate for the first time that BMC elicit an innate immune response via the TRIF pathway and may open the door to novel approaches for immune-based conditioning to promote engraftment. Disclosures: Ildstad: Regenerex: Equity Ownership.

scholarly journals IRF1 Promotes the Innate Immune Response to Viral Infection by Enhancing the Activation of IRF3

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Jingjing Wang ◽  
Huiyi Li ◽  
Binbin Xue ◽  
Rilin Deng ◽  
Xiang Huang ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Critical Role ◽  
Innate Immune ◽  
Host Cells ◽  
Functional Domain ◽  
Phosphatase 2A

ABSTRACT Innate immunity is an essential way for host cells to resist viral infection through the production of interferons (IFNs) and proinflammatory cytokines. Interferon regulatory factor 3 (IRF3) plays a critical role in the innate immune response to viral infection. However, the role of IRF1 in innate immunity remains largely unknown. In this study, we found that IRF1 is upregulated through the IFN/JAK/STAT signaling pathway upon viral infection. The silencing of IRF1 attenuates the innate immune response to viral infection. IRF1 interacts with IRF3 and augments the activation of IRF3 by blocking the interaction between IRF3 and protein phosphatase 2A (PP2A). The DNA binding domain (DBD) of IRF1 is the key functional domain for its interaction with IRF3. Overall, our study reveals a novel mechanism by which IRF1 promotes the innate immune response to viral infection by enhancing the activation of IRF3, thereby inhibiting viral infection. IMPORTANCE The activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. IRF3 plays a critical role in the innate immune response to RNA viral infection. However, whether IRF1 plays a role in innate immunity is unclear. In this study, we demonstrated that IRF1 promotes the innate immune response to viral infection. IRF1 is induced by viral infection. Notably, IRF1 targets and augments the phosphorylation of IRF3 by blocking the interaction between IRF3 and PP2A, leading to the upregulation of innate immunity. Collectively, the results of our study provide new insight into the regulatory mechanism of IFN signaling and uncover the role of IRF1 in the positive regulation of the innate immune response to viral infection.

scholarly journals The role of beneficial bacteria wall elasticity in regulating innate immune response

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Viktoria V. Мokrozub ◽  
Liudmyla M. Lazarenko ◽  
Liubov M. Sichel ◽  
Lidia P. Babenko ◽  
Petro M. Lytvyn ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Beneficial Bacteria

RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

2021 ◽  
Vol 22 ◽  
Author(s):  
Dalia Cicily Kattiparambil Dixon ◽  
Chameli Ratan ◽  
Bhagyalakshmi Nair ◽  
Sabitha Mangalath ◽  
Rachy Abraham ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Innate Immune Response ◽  
Vaccine Development ◽  
Innate Immune ◽  
Interferon Response ◽  
Host Immune System ◽  
Type I ◽  
Adaptive Responses ◽  
Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

scholarly journals Interferon-Stimulated Genes as Enhancers of Antiviral Innate Immune Signaling

2017 ◽  
Vol 10 (2) ◽  
pp. 85-93 ◽  
Author(s):  
Keaton M. Crosse ◽  
Ebony A. Monson ◽  
Michael R. Beard ◽  
Karla J. Helbig
Keyword(s):  
Immune Response ◽  
Viral Infection ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Regulatory Factor ◽  
Interferon Stimulated Genes ◽  
Innate Immune Signaling ◽  
Recent Advancement ◽  
Antiviral Function

The ability of a host to curb a viral infection is heavily reliant on the effectiveness of an initial antiviral innate immune response, resulting in the upregulation of interferon (IFN) and, subsequently, IFN-stimulated genes (ISGs). ISGs serve to mount an antiviral state within a host cell, and although the specific antiviral function of a number of ISGs has been characterized, the function of many of these ISGs remains to be determined. Recent research has uncovered a novel role for a handful of ISGs, some of them directly induced by IFN regulatory factor 3 in the absence of IFN itself. These ISGs, most with potent antiviral activity, are also able to augment varying arms of the innate immune response to viral infection, thereby strengthening this response. This new understanding of the role of ISGs may, in turn, help the recent advancement of novel therapeutics aiming to augment innate signaling pathways in an attempt to control viral infection and pathogenesis.

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